Fever is a prominent sign of many diseases but several aspects of the production of fever in humans remain unknown. Experimental studies in animals suggest that fever is mediated by a small molecular weight protein called leukocytic pyrogen which is synthesized by host phagocytic cells in response to various infectious, toxic or immunologic agents. Although human cells produce leukocytic pyrogen in vitro, many attempts to demonstrate this molecule in vivo during fever in humans have failed. In addition, its specific mechanism of action is poorly understood. We propose to investigate the pathogenesis of fever in humans employing both clinical and laboratory methods. Using the radioimmunoassay for human leukocytic pyrogen recently developed in our laboratory, we intend to measure circulating leukocytic pyrogen in experimentally induced fevers in normal volunteers and in patients with a broad spectrum of disorders. At the same time we will study the clearance of radiolabeled human leukocytic pyrogen in rabbits and correlate this information with human studies. Further experimentation will involve the identification of cellular and subcellular receptors in brain, hypothalamus and other tissues. Coupled with the search for cellular receptors will be studies to uncover the mechanism by which leukocytic pyrogen initiates fever. With the development of purification methods, radiolabeling and production of antibody, these studies on leukocytic pyrogen are now possible. Improvements in the production of human pyrogen, including pyrogen from human lymphoma lines, and characterization will also be continued. The significane of both clinical and laboratory approaches lies in expansion of our understanding of fever in humans as well as possible usefulness in improved diagnostic techniques and the potential development of more specific antipyretic agents.